6,7-ethylene and 6,7-substituted ethylene derivatives of the androstane series



United States Patent "ice 3,470,157 6,7-ETHYLENE AND 6,7-SUBSTITUTEDETHYLENE DERIVATIVES OF THE ANDROSTANE SERIES John A. Zderic, MexicoCity, Mexico, assignor to Syntex Corporation, Apartado, Panama, acorporation of Panama No Drawing. Continuation-impart of applicationSer. No. 544,850, Apr. 25, 1966. This application Apr. 10, 1967, Ser.No. 629,371

Int. Cl. C07c 169/22, 169/24, 173/00 US. Cl. 260-239.55 14 ClaimsABSTRACT OF THE DISCLOSURE 6,7-ethylene and 6,7,-substituted ethylenederivatives of the androstane and l9-nor androstane series havinganabolic activity are prepared by the photochemical cycloaddition of anolefin of the formula:

wherein A is hydrogen or fiuoro, and B is hydrogen, fluoro, chloro,methyl or phenyl, to a 3-keto-A -diene of the androstane, or l9-norandrostane, series.

This is a continuation-in-part of application, Ser. No. 544,850, filedApr. 25, 1966 now abandoned.

This invention relates to nove l cyclopentanopheanthrene derivatives andto a process for the production thereof. More specifically, thisinvention relates to novel 6,7-ethylene and 6,7-substituted ethylenederivatives of the androstane and 19-nor-androstane series.

The compounds of the present invention are represented by the followingformula:

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkylyl orlower haloalkynyl; R is hydrogen, tetrahydropyran-2'-yl or a hydrocarboncarboxylic acyl group of less than 12 carbon atoms; R is hydrogen ormethyl; R is keto or the group in which R is hydrogen,tetrahydropyran-2'-yl or a hydrocarbon carboxylie acyl group of lessthan 12 carbon atoms; A is hydrogen or fluoro; and B is hydrogen,fluoro, chloro, methyl or phenyl.

The wavy line i at C-6 and C-7 indicates both alpha and betaconfigurations for the 6,7-ethylene and 6,7-substituted ethylenederivatives of the present invention, Le.

3,470,157 Patented Sept. 30, 1969 the GaJm-ethylene and6a,7a-substituted ethylene derivatives of the androstane andl9-nor-androstane series along with the 613,7;8-ethylene and6;8,75-substituted ethylene derivatives of the androstane andl9-nor-androstane series.

The hydrocarbon carboxylic acyl groups of the compounds of the presentinvention contain less than 12 carbon atoms and are of a straight,branched, cyclic or cyclic-aliphatic chain structure. This structure issaturated, unsaturated or aromatic and optionally substituted byfunctional groups such as hydroxy, alkoxy containing up to 5 carbonatoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno,and the like. Typical esters thus include acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoaoetate, fl-chloropropionate, adamantoate,and the like.

By the term lower alkyl" is meant a straight or branched chainhydrocarbon group containing up to six carbon atoms and thus includesmethyl, ethyl, n-butyl and the like. By the term "lower alkenyl is meanta straight or branched chain hydrocarbon group containing from 2 to 6carbon atoms and l carbon-carbon double bond; it thus includes vinyl,allyl and the like. By the term lower alkylyl is meant a straight orbranched chain hydrocarbon group containing from 2 to 6 carbon atoms andl carbon-carbon triple bond; it thus includes ethynyl, propargyl and thelike. By the term lower haloalkynyl" is meant an alkynyl group asdefined above which contains one halo substituent, the halo substituenthaving an atomic number of less than 53; it thus includes chloroethynyl,bromethynyl, fiuoroethynyl and the like.

The novel compounds of the present invention possess valuablepharmacological properties. The compounds of the present inventionwherein R is hydrogen, lower alkyl such as methyl, ethyl and the like,or lower alkenyl such as vinyl and the like, are valuableanabolic/androgenic agents having a favorable anabolic/ androgenicratio. The compounds of the present invention wherein R is alkynyl,haloalkynyl and alkenyl, are valuable pituitary inhibiting andprogestational agents and are useful in the treatment of variousmenstrual disorders and in the control and regulation of fertility. Inaddition the novel compounds also possess anti-estrogenic activity.These compounds can be administered via usual routes in pharmaceuticallyacceptable compositions at dosage rates of from 0.5 to 5 mg./kg./day.However, dosage rates below or above this range can be employed, themost favorable dosage rate being conditioned upon the purpose for which'it is administered and the response thereto.

The compounds of the present invention are prepared in accordance withthe following sequence:

wherein R is the group and R R R R A and B are as defined herein-above.

In the practice of the above outlined sequence. a starting material ofFormula I, i.e. an unsubstituted or appropriately substituted S-ketO-M'-diene and an olefin of the formula:

wherein each of A and B is as previously defined, are irradiated withultraviolet light, in an inert organic solvent such as benzene, dioxaneand the like or mixtures thereof, to elfect the photochemicalcycloaddition of the olefin and thereby afford a 6,7-ethylene or6,7-substituted ethylene cycloaddition product as shown by Formula llv Apreferred choice for the photochemical cycloaddition employs benzene andultraviolet light of a wavelength of about 270 to about 330 mu at roomtemperature for a period of about 1 to 12 hours. Any suitable source ofultraviolet irradiation of wavelength of about 270 to about 330 mu canbe employed for the photochemical cycloaddition reaction. Among suchsources are commercially available high pressure mercury vapor lampssuch as a 70 watt Hanau lamp, a 200 watt Hanovia lamp, and the like.

Under the above conditions, the photochemical cycloaddition of theolefin occurs at the 4,5- and 6,7-double bonds of the steroid to afforda mixture of the 4,5- ethylene and 6,7-ethylene adducts when the olefinis ethylene and a mixture of the 4,5-substituted ethylene and6,7-substituted ethylene adducts when the olefin is a substitutedethylene. The orientation of the resulting 4,5- ethylene or4,5-substituted ethylene group with respect to the steroid nucleus isboth alpha and beta, i.e. the products having the 4a,5ot-, 4,8,5;3-, and4 3,5a-configurations. The orientation of the resulting 6,7-ethylene or6,7-substituted ethylene group with respect to the steroid nucleus isboth alpha and beta, i.e. the products having the 6a,7aandfififlfl-configurations, the 6a ,7a-isomer generally being thepredominant product. The mixture of products is routinely separated by aconventional procedure such as by column chromatography to yield the6a,7u-ethylene-, 6;8,7,8-ethylene-, or the 6a,7a-substituted ethyleneand63,7;8-substituted ethylenederivatives of the present invention.

Subsequent to the photochemical cycloaddition, a 3- keto-M-ene-GJ-cycloadduct of Formula II is reduced by treatment with sodium borohydride inisopropanol to afford a corresponding 3fl-hydroxy-M-ene-SJ-cyclo adductof Formula III which is then treated with dihydropyran and an acidcatalyst such as p-toluenesulfonic acid either alone or in an inertorganic cosolvent such as benzene or with a hydrocarbon carboxylic acidanhydride and pyridine in an inert organic solvent to yield a 3,8-(tetrahydropyran-Z-yloxy) or a 3p-acyloxy-6J-cyc1o ad- 4 duct,respectively, each of which is included in Formula III.

As an alternative to the above outlined reaction sequence, a startingmaterial of Formula I containing a free hydroxy group at C-l7 issubjected to photochemical cycloaddition and then is etherified oresterified by c0nventional techniques known to those skilled in the artof steroid chemistry. Thus, for example, following photochemicalcycloaddition, a free I7B-hydroxy containing steroid of Formula II istreated with dihydropyran or a hydrocarbon carboxylic acid anhydride asdescribed hereinabove, to yield the correspondingl7fl-(tetrahydropyran-2'-yloxy) or the corresponding l7;3-(acy1oxy)-6,7-cyclo adduct.

As a further alternative to the above described sequence, a17B-hydr0xy-A -3-keto steroid of Formula ll (ll, R is hydrogen) isreduced by treatment with sodium borohydride, or the like, as describedabove to furnish the corresponding 35,17fl-dihydroxy steroid. Bysubjecting the thus-obtained 3fi,l7;9-diol to the etherification andesterification procedures described above, the corresponding 3B,178-bis(tetrahydropyran-2'-yloxy)- and the corresponding3B,l7[3-bis(acyloxy)-6,7-cyclo adducts, respectively, of Formula [[1 areobtained.

The A -diene starting materials of Formula I are conveniently preparedby treating the corresponding 3-keto- M-ene compound with chloranil in asolvent such as tbutanol, xylene or the like, under reflux for a periodof l to 12 hours.

The following examples are set forth to illustrate but are not intendedto limit the scope of the present invention.

Example 1 A mixture of 2.0 g. of l7fi-hydroxyandrosta-4,6-dien- 3-one inml. of benzene in a Pyrex container is irradiated with a 200 watt highpressure mercury vapor lamp at room temperature for a period of severalhours while bubbling ethylene through the solution. At the end of thereaction time, which is followed by the U.V. spectra, the reactionmixture is evaporated in vacuo to dryness to furnish a residuecontaining the Jar-ethylene adduct, the 43,5;9-ethylene adduct, the4B,5aethylene adduct, the SeJu-ethyIene adduct and the oflflfi-ethyleneadduct of l7fi-hydroxyandrosta-4,6-dien-3-one. The residue is separatedby chromatography on silica eluting with ethylacetatezbenzene to yieldGaJtz-ethyIene-U ihydroxyandrost-4-en-3-one and 65,713 ethylenel7/3-hydroxyandrost-4-en-3-one, each of which is recrystallized frommethanol:methylene chloride.

Utilizing the same procedure, the following starting materials, namely17B-acetoxyandrosta-4,6-dien-3-one;l7,8-(tetrahydropyran-2'-yloxy)androsta4,6-dien-3-onc;17a-methyl-17B-hydroXyandrosta-4,6-dien-3-one;l7ix-ethyl-173-hydroxyandrosta-4,6-dien-3-0ne;l7a-ethynyll7B-hydroxyandrosta-4,6-dien-3-one;17m-methyl-l7fi-hydroxy-19-norandr0sta-4,6-dien-3 -one;l7a-ethyl-17fi-hydroxy-l9-norandrosta-4,6-dien-3-o-ne;l7aethynyl-l7B-hydroxyl 9-norandrosta-4,6-dien-3-one;

and 17fl-hydroxy- 1 9-norandrosta-4,6-dien-3-one;

are converted to the corresponding Mia-ethylene and ofififlethylenecompounds, namely 6a,7a-ethylene-l.7fl-acetoxyandrost-4-en-3-one, andthe GfiJp-isomer;

fiaflwethylene-17B-(tetrahydropyran-Z'-yloxy)androst- 4-en-3-one, andthe 65,7/3-is0me1';

6a,7tx-ethylenel 7a-ethyl- 17 fi-hydroxyandrost-4-en-3-one,

and the 65,7;8-isomer;

6a,7oi-ethylene-l7a-ethynyl-17fl-hydroxyandrost-4-en-3- one, and the613,713-isomer;

6m,7a-ethy1ene-l7a-methy1-17B-hydroxy-19-norandrost-4- en-3-one, and the63,7;3-isomer; 60:,7oc-fitl'1YlBIl6-l7oc-ethyll 7fl-hydroxy-19-norandrost-4- en-3-one, and the 66,7B-isomer;6a,7a-ethylene-l7a-ethynyl-l713-hydroxy-19-norandrost- 4-en-3-one, andthe 65,7;9-isomer; and 611,7 u-ethylene- 1 7 S-hydroxy- 19-norandrost-4-en-3-one,

and the 65,7fl-isomer, respectively.

Example 2 Utilizing the procedure of Example 1 with the exception ofsubstituting tetrafluoroethylene in place of ethylene, the corresponding6a,7a-tetrafluoroethylene and 65,75- tetrafluoroethylene compounds areobtained, namely 6a,7a-tetrafiuoroethylenel7B-hydroxyandrost-4-en-3-one,

and the 65,7[3-isomer;60:,71x-tfitlfiflll0l0fitl'lYl6l'l6-17B-aCBt0XYEtIldl'0St-4-fiI1-3- one,and the 65,7,3-isomer;6a,7a-tetrafluoroethylene-17(8-(tetrahydropyran-2'-yloxyl)androst-4-en-3-one, and the GBJB-isomer;6a,7a-tetrafiuoroethylene-17a-methyl-l7B-hydroxyandr0st-4 en-3-0ne, andthe 65,7;3-isomer;6a,7a-tetrafluoroethylenen-17a-ethyl-17fl-hydroxyandrost- 4-en-3-one,and the 6,3,7B-isomer;6a,7a-tetrafiuoroethylene-l7u-ethynyl-17,8-hydroxyandrost-4-en-3-one,and the 66,7t-l-isomer;6a,?a-tetrafluoroethylene-l7a-hydroxy-l9-norandrost-4- en-3-one, and the6,8,7fi-isomer;6a,7m-tetrafluoroethylene-17a-ethyl-l7B-hydroxy-l9-norandrost-4-en-3-one,and the 613,7;8-isomer;611,7a-tetrafluoroethylene-l7a-ethynyl-l7B-hydroxy-l9-norandrost-4-en-3-one, and the 63,7(3-isomer; and611,7a-tetratluoroethylene-1'lfi-hydroxy-l9-norandrost-4- en-3-one, andthe 65,7;9-isomer, respectively.

Example 3 Utilizing the procedure of Example 1, the following startingmaterials are reacted with the olefin as indicated to afford the6a,7a-Substltut6d ethylene and 65,75-substituted ethylene compounds ofthe present invention, namely Two milliliters of dihydropyran are addedto a solution of 1 g. of 6a,7a-ethylene-17fl-hydroxy-l9-norandrost-4-en-3-one in 15 ml. of benzene. About 1 ml. is removed by distillationto remove moisture and 0.4 g. of p-toluenesulfonic acid is added to thecooled solution. This mixture is allowed to stand at room temperaturefor four days, and is then washed with aqueous sodium carbonate solutionand water, dried and evaporated. The residue is chromatographed onneutral alumina, eluting with hexane, to yield6a,7u-ethylene-17B-(tetrahydropyran-2'-yloxy)- 19-norandrost-4-en-3-onewhich is recrystallized from pentane.

Utilizing the above procedure, the following starting materials,

6a,7a-ethylene-l75-hydroxyandrost-4-en-3-one;

6u,7a-tetrafluoroethylene-lYB-hydroxy-l9-norandrost-4- en-3-one;

afla-tetrafluoroethylene-l7p-hydroxyandrost-4-en-3- one; and

are converted to the corresponding l7fi-(tetrahydropyran- 2-yloxy)compounds, namely 6u,7a-ethylene-l7fl- (tetrahydropyran-2'-yloxy)androst-4- en-3-one;

6a,7a-tetrafluoroethylene-l7fi-(tetrahydropyran-T-yloxy)-l9-norandrost-4-en-3-one;

6a,7a-tetrafiuoroethylene-l 7,B(tetrahydropyran-2'-yloxy)androst-4-en-3-one; and

6a,7a(l',2'-difiuoro)ethylene-lh-allyl-l7B-tetrahydropyran-2'-yloxy)-19-norandrost-4-en-3-one;respectively.

By repeating the above procedure with the GflJB-isomer of the abovestarting materials, there are obtained the corresponding 6fi,7,B-isomersof the above final products.

Example 5 A mixture of 1 g. of fiafla-ethylene-l7fi-hydroxy-l9-norandrost 4-en-3-one, 4 ml. of pyridine and 2 ml. of acetic anhydrideis allowed to stand at room temperature for 15 hours. The mixture isthen poured into ice water and the solid which forms is collected byfiltration, washed with water, and dried to yield6u,7a-ethylene-17flacetoxy-l9-norandrost-4-en-3-one which can be furtherpurified through recrystallization from acetone:hexane.

Utilizing the above procedure, the novel starting material is treatedwith propionic anhydride, caproic anhydride, enanthic anhydride, andcyclopentylpropionic anhydride, respectively, to obtain thel7fi-propionate, 1713- caproate, l7fi-enanthate, and17fl-cyclopentylpropionate, respectively.

By repeating the above procedure with the 65,7,3-isomer, there areobtained the corresponding GBJfi-final products.

Example 6 A mixture of 1 g. of sodium borohydride in 3 ml. of water isadded to an ice-cooled solution of 1 g. of 6a.,7atetrafluoroethylene 173hydroxyandrost-4-en-3-one in ml. of methanol and the mixture is thenallowed to stand for 16 hours at room temperature. The excess reagent isdecomposed by addition of acetic acid and the mixture is thenconcentrated to a small volume in vacuo and diluted with water. Theproduct is extracted with ethyl acetate and these extracts are washedwith water, dried and evaporated to yieldfiefla-tetrafiuoroethyleneandrost-4-en-3p,17;3-diol which may be furtherpurified by recrystallization from acetonczhexane.

Four milliliters of dihydropyran are added to a solution of 1 g. of6a,7a tetrafluoroethyleneandrost-4-en-35,17B- diol in 15 ml. of benzene.About 1 m1. is removed by distillation to remove moisture and 0.5 g. ofp-toluenesulfonic acid is added to the cooled solution. This mixture isallowed to stand at room temperature for four days, and is then washedwith aqueous sodium carbonate solution and Water, dried and evaporated.The residue is chromatographed on neutral alumina, eluting with hexane,to yield 6a,7crtetrafiuoroethylene-ZfiJ7l3-bis(tetrahydropyran-2'-yloxy)androst-4-enewhich is recrystallized from pentane.

By repeating the above procedure with the 6,3,7B-iso mer, there isobtained the corresponding fififlp-final prod- 7 net, namely 613,75tetrafluoroethylene-Zifl,1718-bis(tetrahydropyran-2'-yloxy)androst-4-ene.

Example 7 Utilizing the reduction step of Example 6, 6a,7u-ethylene 17ccethynyl 17fl-hydroxy-l9norandrost-4-en-3- one is converted to thecorresponding 35,17,6-diol.

A mixture of l g. of6a,7a-ethylene-l7a-ethynyl-19-norandrost-4-ene-3B,17B-diol, 4 ml. ofpyridine and 4 ml. of acetic anhydride is allowed to stand at roomtemperature for 15 hours. The mixture is then poured into ice water andthe solid which forms is collected by filtration, washed with water, anddried to yield 35,17 3 diacetoxy- 611,70;ethylene-l7a-ethynyl-19-norandrost-4-ene which can be further purifiedthrough recrystallization from acetone:hexane.

By repeating the above procedure with the 619,7(3-isomer, there isobtained the corresponding 65,7;3-final product, namely313,l7fi-diacetoxy-6B,7,6-ethylene 17a ethynyl-l9-norandrost-4-ene.

By repeating the above procedure with the exception of substitutingcaproic anhydride and then proprionic anhydride in place of aceticanhydride, there are obtained the corresponding 35,1713-dicaproates and3,8,17,3-diproprionates, respectively.

Example 8 A mixture of 2 g. of l7u-ethynyl-l7B-hydroxy-19-norandrosta4,6 diene-3-one and S g. of 1,2-dichloroethylene in a Pyrex container in140 ml. of benzene is irradiated with a 200 watt high pressure mercurylamp with a Pyrex filter at room temperature for a period of threehours. After the end of the reaction, the mixture of reaction productsis evaporated to dryness to furnish a residue containing the 4a,5a(l',2'-dichloro)ethylene adduct, the 4 3,55 (1,2'-dichloro)ethyleneadduct, the 45, 5a (1,2'-dichloro)ethylene adduct, the6a,7nt-(1',2'-(lichloro)ethylene adduct, the 6;],75(1',2'-dichloro)ethylene adduct of 17a ethynyl 17/9hydroxy-19-norandrosta 4,6-diene-3-one. The residue is separated bychromatography on silica eluting with ethyl acetate:benzene to yield6a,7m (1',2'-dichloro)ethylene-l7a-ethynyl 17Bhydroxy-l9-norandrost-4-en-3-one and 613,718- (1',2' dichloro)ethylene17a-ethynyl-l7fl-hydroxy-l9- norandrost 4-en-3-one, each of which isrecrystallized from methanolzmethylene chloride.

Utilizing the above procedure, the following starting materials arereacted with the following olefins to afford the 6u,7a-substituted and6fi,7}8-substituted ethylene derivatives as indicated below.

Olefin Final product Stilbene 6,7a-(l',2'-diphenyl)ethylene-l7a-methyll7fl-hydroxyandrost-4- en-3-one and the GBJfi-isomer.

Starting material 17a-methyl-17B-hydroxyandrosta-4,G-dion-3-one.

8 Example 10 Utilizing the procedure of Example 6,fiaflm-ethylenel7fi-acetoxyandrost-4-en-3-one is converted to thecorresponding 35(tetrahydropyran-2-yloxy)-6a,7a-ethylenel7fl-acetoxyandrost-4-ene.

By repeating the above procedure with the 63,7 3- isomer of the abovestarting material, there is obtained the corresponding 65,7;8-finalproduct, namely Pip-(tetrahydropyran-2-yloxy)65,718 ethylene 1718acetoxyandrost-4-ene.

Example 11 Utilizing the reduction step of Example 6,6a,7u-ethylene-l7fl-(tetrahydropyran 2' yloxy)androst-4-en-3-one isconverted to the corresponding3fi-hydroxy-6a,7a-ethylene-l7B-(tetrahydropyran-2'-yloxy)androst-4-ene.

Utilizing the esterification reaction of Example 5 with aceticanhydride, the latter 3B-hydroxy compound is converted to thecorresponding3B-acetoxy-6a,7a-ethylenel7/8-(tetrahydropyran-2'-yloxy)androst-4-ene.

By repeating the above procedure with the 66,718- isomer, there isobtained the corresponding 6;8,7}8-final product, namely 3/3acetoxy-65Jfi-ethylene-l7B-(tetrahydropyran-2-yloxy)androst-4-ene.

Example 12 A solution of 1 g. of 3B-(tetrahydropyran-2'-yloxy)-GaJa-ethylene-17-;3-acetoxyandrost 4 ene in 50 ml. of methanol is heatedat reflux for three hours with a solution of potassium hydroxide in 1ml, of water. The reaction mixture is then poured into ice water and thesolid which forms is collected by filtration, washed with water toneutrality and dried to yield 3fl-(tetrahydropyran-2'-yloxy)-6a,7a-ethylene-l7fl-hydroxyandrost-4-ene which is recrystallizedfrom methylene chloridezether.

By repeating the above procedure with the 66,7B-isomer of the abovestarting material, there is obtained the corresponding3B-(tetrahydropyran 2' yloxy)-6B,7p-ethylene-l7fi-hydroxyandrost-4-ene.

Example 13 To a mixture of 1 g. of3B-acetoxy-6ni,7m-ethylenel7B-(tetrahydropyran-2-yloxy)andr0st-4-ene in30 ml. of acetic acid is added 0.5 ml. of 2 N hydrochloric acid. Themixture is allowed to stand five hours at room temperature and thendiluted with ice water and extracted several times with methylenechloride. The combined extracts are washed with water to neutrality,dried over sodium sulfate and evaporated to dryness to yield 35-acetoxy-6a,7a-ethylene-17B hydroxyandrost-4-ene which is recrystallizedfrom acetone:hexane.

By repeating the above procedure with the 6;9,7fi isomer of the abovestarting material, there is obtained the corresponding 3;?! acetoxy619,75 ethy1ene-17fl-hydroxyandrost-4-ene.

What is claimed is:

l. A compound of the formula:

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl orlower haloalkynyl;

R is hydrogen, tetrahydropyran-2-yl or a hydrocarbon carboxylic acylgroup of less than 12 carbon atoms;

R is hydrogen or methyl; R is keto or the group H R oin which R ishydrogen, tetrahydropyran-2'-yl or a hydrocarbon carboxylic acyl groupof less than 12 carbon atoms;

A is hydrogen or fluoro; and

B is hydrogen, fiuoro, chloro, methyl or phenyl.

2. A compound according to claim 1 wherein R is hydrogen, methyl, ethylor ethynyl; R is hydrogen, tetrahydropyran-2'-yl or acetyl; and each ofA and B is hydrogen or fluoro.

3. A compound according to claim 2 wherein each of R R and R ishydrogen; R is keto; and each of A and B is hydrogen.

4. A compound according to claim 2 wherein each of R and R is hydrogen;R is methyl; R is keto; and each of A and B is hydrogen.

5. A compound according to claim 2 wherein each of R and R is hydrogen;R is tetrahydropyran-2-yl; R is keto; and each of A and B is hydrogen.

6. A compound according to claim 2 wherein R is hydrogen; R istetrahydropyran-2'-yl; R is methyl; R is keto; and each of A and B ishydrogen.

7. A compound according to claim 2 wherein R is ethynyl; R is hydrogen;R is methyl; R is keto; and each of A and B is hydrogen.

8. A compound according to claim 2 wherein R is ethynyl; each of R and Ris hydrogen; R is keto; and each of A and B is fluoro.

9. A compound according to claim 2 wherein R is ethyl; each of R and Ris hydrogen; R is keto; and each of A and B is hydrogen.

10. A compound according to claim 2 wherein R is ethyl; each of R and Ris hydrogen; R is keto; and each of A and B is fluoro.

11. A compound according to claim 2 wherein each of R R and R ishydrogen; R is keto; and each of A and B is fluoro.

12. A compound according to claim 2 wherein each of R and R is hydrogen;R is methyl; R is keto; and each of A and B is fluoro.

13. A compound according to claim 2 wherein each of R and R is hydrogen;R is tetrahydropyran-2'-yl; R is keto; and each of A and B is fluoro.

14. A compound according to claim 2 wherein R is hydrogen; R istetrahydropyran-2'-yl; R is methyl; R is keto; and each of A and B isfluoro.

References Cited UNITED STATES PATENTS 3,356,677 12/1967 Beard et a].

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 3,470,157Dated September 30, 1969 Inventor(s) John A. Zderic It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, lines 37 through 49, the formula should appear as follows:

ASEFA SIGNED AND SEALED 23 (SM, JUN 1910 Axteat:

Edward M. Flet her, 1', W W, R Auesfing Officer fiomlsaioner of Patents

